We formed the C. elegans Gene Knockout Consortium in 1998. From the beginning, the goal of the consortium was to produce targeted genetic knockouts at a rate to satisfy the needs of the C. elegans research community. At present, this need is greater than our present production capacity. We therefore propose a three-fold scale up of the project. We can accomplish this by building a highly automated platform for the growth and manipulation of C. elegans, and for the high throughput assembly and analysis of PCR reactions. This platform will increase our productivity, and allow for the generation of 4,000 genetic mutants over four years. More then this, however, the platform can be applied generally to other proposed C. elegans genomically scaled projects such as the systematic growth and expression profiling of knockout mutants and, as new phenotypic assays are proposed, the systematic phenotyping of worms treated with RNAi or chemical compounds. Our current gene knockout methods are designed to detect deletions. Point mutations, however, provide research opportunities beyond that of deletions. We therefore propose research to develop relatively low cost methods for the targeted detection of point mutations in C. elegans. This work supports and promotes the powerful genetic methods available for the study of C. elegans and it likely will lead to research that, realistically, would not take place if the expense and effort to make such gene knockouts were to be borne exclusively by individual investigators. Further, our research should not only be relevant to high throughput reverse-genetics, but will also enable more penetrating genetic studies in individual laboratories. The ready availability of our proposed resource will accelerate the investigation of protein function as it relates to the development and physiology of C. elegans and to the homologous processes found in humans.